tbuckley/cabot-search huggingface dataset:
Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes
Authors: Navonil De Sarkar, Robert D. Patton, Anna-Lisa Doebley, Brian Hanratty, Mohamed Adil, Adam J. Kreitzman, Jay F. Sarthy, Minjeong Ko, Sandipan Brahma, Michael P. Meers, Derek H. Janssens, Lisa S. Ang, Ilsa M. Coleman, Arnab Bose, Ruth F. Dumpit, Jared M. Lucas, Talina A. Nunez, Holly M. Nguyen, Heather M. McClure, Colin C. Pritchard, Michael T. Schweizer, Colm Morrissey, Atish D. Choudhury, Sylvan C. Baca, Jacob E. Berchuck, Matthew L. Freedman, Kami Ahmad, Michael C. Haffner, R. Bruce Montgomery, Eva Corey, Steven Henikoff, Peter S. Nelson, Gavin Ha
Journal: Cancer Discovery (2022)

Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology.This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517.
RAB25 coordinates filaggrin‐containing keratohyalin granule maturation and affects atopic dermatitis severity
Authors: Haengdueng Jeong, Nakyum Lee, Chanyang Uhm, Kyungrae Cho, Heeju Oh, Yeseul Oh, KeLun Zhang, Hye Li Kim, James R. Goldenring, Kyung‐Min Lim, Chang Ook Park, Ki Taek Nam
Journal: Allergy (2022)

Keratohyalin granules (KHGs) supply the critical epidermal protein constituents such as filaggrin for maintaining skin barrier function during epidermal differentiation; however, their regulating mechanism remains largely unelucidated.To investigate the role of Ras-related protein Rab-25 (RAB25) expression in skin disease, we utilized skin specimens of patients with moderate-to-severe atopic dermatitis (AD) and healthy controls. To investigate the susceptibility of Rab25 knockout mice to AD, we established an oxazolone-induced AD model.We investigated the role of RAB25 in KHG maturation and AD. RAB25-deficient mice showed a disrupted stratum corneum along with skin barrier dysfunction, decreased KHG production, and abnormal KHG processing. Consistently, in the human keratinocyte cell line HaCaT, RAB25 co-expressed with filaggrin-containing KHG and RAB25 silencing impaired KHG formation, which was attributable to abnormal actin dynamics. Most importantly, RAB25 expression was severely downregulated in the skin lesions of patients with AD, which was strongly correlated with disease severity scores.RAB25 coordinates KHG homeostasis by regulating actin dynamics and is critical for epidermal differentiation and the pathophysiology of AD.
European Haplotype of <i>Echinococcus multilocularis</i> in the United States
Authors: Louis B Polish, Elise M O'Connell, Thomas F E Barth, Bruno Gottstein, Anne Zajac, Pamela C Gibson, Aissatou Bah, Megan Kirchgessner, Marko Estrada, M Alexis Seguin, Roger Ramirez-Barrios
Journal: New England Journal of Medicine (2022)

European Haplotype of Echinococcus multilocularis in the United StatesTo the Editor: Alveolar echinococcosis caused by Echinococcus multilocularis, a small cyclophyllid tapeworm, is a severe parasitic disease in humans.Two years after the diagnosis of a European haplotype of E. multilocularis in a patient in Vermont (Patient VT1) who did not have a history of exposure to alveolar echinococcosis abroad, 1 the disease was diagnosed in a second patient in Vermont (Patient VT2), who also did not have such exposure history.Details regarding the two cases are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.Patient VT2 was an 82-year-old man with memory decline who presented with painless jaundice.The laboratory evaluation revealed a total bilirubin level of 15.4 mg per deciliter (263 μmol per liter), an alkaline phosphatase level of 573 U per liter, an aspartate aminotransferase level of 156 U per liter, and an alanine aminotransferase level of 190 U per liter.Abdominal computed tomography revealed a mass-like hypodensity in the right lobe of the liver with intrahepatic biliary ductal dilatation and mass effect on the inferior vena cava.Biopsy of the mass revealed
Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer
Authors: Katrin J. Frank, Antonio Mulero-Sánchez, Alexandra Berninger, Laura Ruiz-Cañas, Astrid Bosma, Kıvanç Görgülü, Nan Wu, Kalliope N. Diakopoulos, Ezgi Kaya-Aksoy, Dietrich A. Ruess, Derya Kabacaoğlu, Fränze Schmidt, Larissa Kohlmann, Olaf van Tellingen, Bram Thijssen, Marieke van de Ven, Natalie Proost, Susanne Kossatz, Wolfgang A. Weber, Bruno Sainz, Rene Bernards, Hana Algül, Marina Lesina, Sara Mainardi
Journal: Cell Reports Medicine (2022)

Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro, superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC.
A polyamine-centric, blood-based metabolite panel predictive of poor response to CAR-T cell therapy in large B cell lymphoma
Authors: Johannes F. Fahrmann, Neeraj Y. Saini, Chang Chia-Chi, Ehsan Irajizad, Paolo Strati, Ranjit Nair, Luis E. Fayad, Sairah Ahmed, Hun Ju Lee, Swaminathan Iyer, Raphael Steiner, Jody Vykoukal, Ranran Wu, Jennifer B. Dennison, Loretta Nastoupil, Preetesh Jain, Michael Wang, Michael Green, Jason Westin, Viktoria Blumenberg, Marco Davila, Richard Champlin, Elizabeth J. Shpall, Partow Kebriaei, Christopher R. Flowers, Michael Jain, Robert Jenq, Christoph K. Stein-Thoeringer, Marion Subklewe, Sattva S. Neelapu, Sam Hanash
Journal: Cell Reports Medicine (2022)

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed or refractory (r/r) large B cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether an MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme that regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers that resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine, and lysophospholipids, which was validated in an independent set from another institution as predictive of non-durable response to CAR-T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL.
Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants, and therapeutically relevant pathways
Authors: Anthony R. Soltis, Nicholas W. Bateman, Jianfang Liu, Trinh Nguyen, Teri J. Franks, Xijun Zhang, Clifton L. Dalgard, Coralie Viollet, Stella Somiari, Chunhua Yan, Karen Zeman, William J. Skinner, Jerry S.H. Lee, Harvey B. Pollard, Clesson Turner, Emanuel F. Petricoin, Daoud Meerzaman, Thomas P. Conrads, Hai Hu, Rebecca Blackwell, Gauthaman Sukumar, Dagmar Bacikova, Camille Alba, Elisa McGrath, Sraavya Polisetti, Meila Tuck, Alden Chiu, Gabe Peterson, Caroline Larson, Leonid Kvecher, Brenda Deyarmin, Jennifer Kane, Katie Miller, Kelly A. Conrads, Brian L. Hood, Sasha C. Makohon-Moore, Tamara S. Abulez, Elisa Baldelli, Mariaelena Pierobon, Qing-rong Chen, Henry Rodriguez, Sean E. Hanlon, Anthony R. Soltis, Nicholas W. Bateman, Jianfang Liu, Trinh Nguyen, Teri J. Franks, Xijun Zhang, Clifton L. Dalgard, Coralie Viollet, Stella Somiari, Chunhua Yan, Karen Zeman, William J. Skinner, Jerry S.H. Lee, Harvey B. Pollard, Clesson Turner, Emanuel F. Petricoin, Daoud Meerzaman, Thomas P. Conrads, Hai Hu, Craig D. Shriver, Christopher A. Moskaluk, Robert F. Browning, Matthew D. Wilkerson, Craig D. Shriver, Christopher A. Moskaluk, Robert F. Browning, Matthew D. Wilkerson
Journal: Cell Reports Medicine (2022)

We present a deep proteogenomic profiling study of 87 lung adenocarcinoma (LUAD) tumors from the United States, integrating whole-genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry, and reverse-phase protein arrays. We identify three subtypes from somatic genome signature analysis, including a transition-high subtype enriched with never smokers, a transversion-high subtype enriched with current smokers, and a structurally altered subtype enriched with former smokers, TP53 alterations, and genome-wide structural alterations. We show that within-tumor correlations of RNA and protein expression associate with tumor purity and immune cell profiles. We detect and independently validate expression signatures of RNA and protein that predict patient survival. Additionally, among co-measured genes, we found that protein expression is more often associated with patient survival than RNA. Finally, integrative analysis characterizes three expression subtypes with divergent mutations, proteomic regulatory networks, and therapeutic vulnerabilities. This proteogenomic characterization provides a foundation for molecularly informed medicine in LUAD.
Phase 1 multicenter, dose-expansion study of ARX788 as monotherapy in HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma
Authors: Yang Zhang, Miao-Zhen Qiu, Ju-Feng Wang, Yan-Qiao Zhang, Ao Shen, Xiang-Lin Yuan, Tao Zhang, Xiao-Li Wei, Hong-Yun Zhao, De-Shen Wang, Qi Zhao, Gao-Zhun Xiong, Yan-Ping Ji, Xue-Jun Liang, Gang Xia, Rui-Hua Xu
Journal: Cell Reports Medicine (2022)

ARX788 is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate with AS269 as cytotoxic payload. In this phase 1 multicenter dose-expansion clinical trial, patients with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma failing to respond to prior trastuzumab-based standard treatment were enrolled. Between July 15th, 2019, and March 14th, 2022, 30 participants were enrolled. Twenty-eight (93.3%) patients experienced at least one drug-related adverse event (AE) and 13.3% experienced grade 3 ARX788-related AEs. The confirmed objective response rate is 37.9% (95% confidence interval [CI]: 20.7%–57.7%) and the disease control rate is 55.2% (95% CI: 35.7%–73.6%). With a median follow up of 10 months, the median progression-free survival and overall survival are 4.1 (95% CI: 1.4–6.4) and 10.7 months (95% CI: 4.8–not reached), respectively. The median duration of response is 8.4 (95% CI: 2.1–18.9) months. ARX788 is well tolerated and has promising anti-tumor activity in patients with HER2-positive advanced gastric adenocarcinoma (ChinaDrugTrials.org.cn: CTR20190639).
Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis
Authors: Rebeca Uceda-Castro, Andreia S. Margarido, Lesley Cornet, Serena Vegna, Kerstin Hahn, Ji-Ying Song, Diana A. Putavet, Mariska van Geldorp, Ceren H. Çitirikkaya, Peter L.J. de Keizer, Leon C. ter Beek, Gerben R. Borst, Leila Akkari, Olaf van Tellingen, Marike L.D. Broekman, Claire Vennin, Jacco van Rheenen
Journal: Cell Reports Medicine (2022)

An increasing number of breast cancer patients develop brain metastases (BM). Standard-of-care treatments are largely inefficient, and breast cancer brain metastasis (BCBM) patients are considered untreatable. Immunotherapies are not successfully employed in BCBM, in part because breast cancer is a "cold" tumor and also because the brain tissue has a unique immune landscape. Here, we generate and characterize immunocompetent models of BCBM derived from PyMT and Neu mammary tumors to test how harnessing the pro-senescence properties of doxorubicin can be used to prime the specific immune BCBM microenvironment. We reveal that BCBM senescent cells, induced by doxorubicin, trigger the recruitment of PD1-expressing T cells to the brain. Importantly, we demonstrate that induction of senescence with doxorubicin improves the efficacy of immunotherapy with anti-PD1 in BCBM in a CD8 T cell-dependent manner, thereby providing an optimized strategy to introduce immune-based treatments in this lethal disease. In addition, our BCBM models can be used for pre-clinical testing of other therapeutic strategies in the future.
Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes
Authors: Absalon D. Gutierrez, Zhanguo Gao, Vala Hamidi, Liang Zhu, Karla Bermudez Saint Andre, Kayla Riggs, Monika Ruscheinsky, Hongyu Wang, Yongmei Yu, Charles Miller, Hernan Vasquez, Heinrich Taegtmeyer, Mikhail G. Kolonin
Journal: Cell Reports Medicine (2022)

Mechanisms underlying anti-diabetic effects of GLP1 analogs remain incompletely understood. We observed that in prediabetic humans exenatide treatment acutely induces interleukin-6 (IL-6) secretion by monocytes and IL-6 in systemic circulation. We hypothesized that GLP1 analogs signal through IL-6 in adipose tissue (AT) and used the mouse model to test if IL-6 receptor (IL-6R) signaling underlies the effects of the GLP1-IL-6 axis. We show that liraglutide transiently increases IL-6 in mouse circulation and IL-6R signaling in AT. Metronomic liraglutide treatment resulted in AT browning and thermogenesis linked with STAT3 activation. IL-6-blocking antibody treatment inhibited STAT3 activation in AT and suppressed liraglutide-induced increase in thermogenesis and glucose utilization. We show that adipose IL-6R knockout mice still display liraglutide-induced weight loss but lack thermogenic adipocyte browning and metabolism activation. We conclude that the anti-diabetic effects of GLP1 analogs are mediated by transient upregulation of IL-6, which activates canonical IL-6R signaling and thermogenesis.
Challenges in glioblastoma research: focus on the tumor microenvironment
Authors: Andreas Bikfalvi, Cristine Alves da Costa, Tony Avril, Jean-Vianney Barnier, Luc Bauchet, Lucie Brisson, Pierre Francois Cartron, Hélène Castel, Eric Chevet, Hervé Chneiweiss, Anne Clavreul, Bruno Constantin, Valérie Coronas, Thomas Daubon, Monique Dontenwill, Francois Ducray, Natacha Entz-Werlé, Dominique Figarella-Branger, Isabelle Fournier, Jean-Sébastien Frenel, Mathieu Gabut, Thierry Galli, Julie Gavard, Gilles Huberfeld, Jean-Philippe Hugnot, Ahmed Idbaih, Marie-Pierre Junier, Thomas Mathivet, Philippe Menei, David Meyronet, Céline Mirjolet, Fabrice Morin, Jean Mosser, Elisabeth Cohen-Jonathan Moyal, Véronique Rousseau, Michel Salzet, Marc Sanson, Giorgio Seano, Emeline Tabouret, Aurélie Tchoghandjian, Laurent Turchi, Francois M. Vallette, Somya Vats, Maité Verreault, Thierry Virolle
Journal: Trends in cancer (2022)
Case 35-2022: A 60-Year-Old Man with Progressive Dyspnea, Neck Swelling, and a Lung Mass
Authors: Jennifer S. Temel, David M. Dudzinski, Subba R. Digumarthy, Colleen M. Keyes, Florence K. Keane, Daniel Shepherd
Journal: New England Journal of Medicine (2022)

A 60-year-old man was evaluated for dyspnea, neck swelling, and a lung mass. Chest imaging revealed a mass in the hilar region of the right upper lobe and mass effect. Management decisions were made.
Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial
Authors: Konstantinos Leventogiannis, Evdoxia Kyriazopoulou, Nikolaos Antonakos, Antigone Kotsaki, Iraklis Tsangaris, Dimitra Markopoulou, Inge Grondman, Nikoleta Rovina, Vassiliki Theodorou, Eleni Antoniadou, Ioannis Koutsodimitropoulos, George Dalekos, Glykeria Vlachogianni, Karolina Akinosoglou, Vassileios Koulouras, Apostolos Komnos, Theano Kontopoulou, Athanassios Prekates, Antonia Koutsoukou, Jos W.M. van der Meer, George Dimopoulos, Miltiades Kyprianou, Mihai G. Netea, Evangelos J. Giamarellos-Bourboulis
Journal: Cell Reports Medicine (2022)

The state of immune activation may guide targeted immunotherapy in sepsis. In a double-blind, double-dummy randomized clinical study, 240 patients with sepsis due to lung infection, bacteremia, or acute cholangitis were subjected to measurements of serum ferritin and HLA-DR/CD14. Patients with macrophage activation-like syndrome (MALS) or immunoparalysis were randomized to treatment with anakinra or recombinant interferon-gamma or placebo. Twenty-eight-day mortality was the primary endpoint; sepsis immune classification was the secondary endpoint. Using ferritin >4,420 ng/mL and <5,000 HLA-DR receptors/monocytes as biomarkers, patients were classified into MALS (20.0%), immunoparalysis (42.9%), and intermediate (37.1%). Mortality was 79.1%, 66.9%, and 41.6%, respectively. Survival after 7 days with SOFA score decrease was achieved in 42.9% of patients of the immunotherapy arm and 10.0% of the placebo arm (p = 0.042). Three independent immune classification strata are recognized in sepsis. MALS and immunoparalysis are proposed as stratification for personalized adjuvant immunotherapy. Clinicaltrials.gov registration NCT03332225.
Cross-reactive SARS-CoV-2 epitope targeted across donors informs immunogen design
Authors: Blake M. Hauser, Jared Feldman, Maya Sangesland, Larance Ronsard, Kerri J. St. Denis, Maegan L. Sheehan, Yi Cao, Julie Boucau, Ian W. Windsor, Agnes H. Cheng, Mya L. Vu, Marcella R. Cardoso, Ty Kannegieter, Alejandro B. Balazs, Daniel Lingwood, Wilfredo F. Garcia-Beltran, Aaron G. Schmidt
Journal: Cell Reports Medicine (2022)

The emergence of the antigenically distinct and highly transmissible Omicron variant highlights the possibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune escape due to viral evolution. This continued evolution, along with the possible introduction of new sarbecoviruses from zoonotic reservoirs, may evade host immunity elicited by current SARS-CoV-2 vaccines. Identifying cross-reactive antibodies and defining their epitope(s) can provide templates for rational immunogen design strategies for next-generation vaccines. Here, we characterize the receptor-binding-domain-directed, cross-reactive humoral repertoire across 10 human vaccinated donors. We identify cross-reactive antibodies from diverse gene rearrangements targeting two conserved receptor-binding domain epitopes. An engineered immunogen enriches antibody responses to one of these conserved epitopes in mice with pre-existing SARS-CoV-2 immunity; elicited responses neutralize SARS-CoV-2, variants, and related sarbecoviruses. These data show how immune focusing to a conserved epitope targeted by human cross-reactive antibodies may guide pan-sarbecovirus vaccine development, providing a template for identifying such epitopes and translating to immunogen design.
Daily activity timing in the Anthropocene
Authors: Neil A. Gilbert, Kate A. McGinn, Laura A. Nunes, Amy A. Shipley, Jacy Bernath-Plaisted, John D.J. Clare, Penelope W. Murphy, Spencer R. Keyser, Kimberly L. Thompson, Scott B. Maresh Nelson, Jeremy M. Cohen, Ivy V. Widick, Savannah L. Bartel, John L. Orrock, Benjamin Zuckerberg
Journal: Trends in Ecology & Evolution (2022)
In vivo partial reprogramming by bacteria promotes adult liver organ growth without fibrosis and tumorigenesis
Authors: Samuel Hess, Timothy J. Kendall, Maria Pena, Keitaro Yamane, Daniel Soong, Linda Adams, Richard Truman, Anura Rambukkana
Journal: Cell Reports Medicine (2022)

Ideal therapies for regenerative medicine or healthy aging require healthy organ growth and rejuvenation, but no organ-level approach is currently available. Using Mycobacterium leprae (ML) with natural partial cellular reprogramming capacity and its animal host nine-banded armadillos, we present an evolutionarily refined model of adult liver growth and regeneration. In infected armadillos, ML reprogram the entire liver and significantly increase total liver/body weight ratio by increasing healthy liver lobules, including hepatocyte proliferation and proportionate expansion of vasculature, and biliary systems. ML-infected livers are microarchitecturally and functionally normal without damage, fibrosis, or tumorigenesis. Bacteria-induced reprogramming reactivates liver progenitor/developmental/fetal genes and upregulates growth-, metabolism-, and anti-aging-associated markers with minimal change in senescence and tumorigenic genes, suggesting bacterial hijacking of homeostatic, regeneration pathways to promote de novo organogenesis. This may facilitate the unraveling of endogenous pathways that effectively and safely re-engage liver organ growth, with broad therapeutic implications including organ regeneration and rejuvenation.